The embolization of a blood vessel is important in preventing/controlling bleeding (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm) or to ablate diseased tissue (e.g., tumors, etc.) by cutting off its blood supply.
Endovascular embolization of blood vessels is known to be conducted as alternative to surgical interventions for a variety of purposes including the endovascular treatment of tumors, the treatment of lesions such as aneurysms, arteriovenous malformations, arteriovenous fistula, uncontrolled bleeding and the like.
Endovascular embolization of blood vessels is accomplished via catheter techniques which permit the selective placement of the catheter at the vascular site to be embolized.
Recent techniques proposed to embolize blood vessels by using injectable embolizing compositions including polymeric materials as embolizing agents.
The use of embolizing compositions in the treatment of aneurysms or arteriovenous malformations (AVMs) is advantageous since the polymeric materials fill the inside of the aneurysms or AVM and solidify in the shape of the aneurysm or AVM, therefore the aneurysm or AVM will be completely excluded from the blood circulation.
It is also known that injectable embolizing compositions containing polymeric materials as embolizing agents may be used for treating tumors by direct puncture. In such a case, the embolizing composition is directly injected into the tumoral tissue or the vascular bed surrounding the tumor via a needle technology.
Known polymeric materials employed in embolizing compositions include for example those wherein a preformed polymer in situ precipitates from a carrier solution at the vascular site or into the tumor.
In embolizing compositions, the preformed polymer must be selected to be capable of rapid precipitation to form a well defined cohesive solid or semi-solid mass, space-filling material upon contact with blood or any other body aqueous environment in a tissue.
Additionally, these compositions should be sterile, stable, biocompatible, and further highly radiopaque to allow for an efficient imaging using current radiology techniques.
This last property is necessary in order to visualize the embolizing composition during injection, deposition into the vascular site, and clinical follow-up.
A number of documents disclose liquid formulations intended for the embolization of blood vessels and containing a water-insoluble, organo-soluble biocompatible preformed polymer dissolved in a biocompatible water-miscible organic solvent, and a solid water-insoluble biocompatible radiopaque contrast agent such as tantalum, tantalum oxide, tungsten, bismuth trioxide and barium sulfate.
These known radiopaque embolizing compositions, precipitating upon contact with blood, are simple physical mixtures of a preformed polymer dissolved in a water-miscible organic solvent and a conventional radiopaque contrast agent.
U.S. Pat. No. 5,580,568 discloses compositions suitable for use in embolizing blood vessels which comprise a cellulose diacetate polymer, a biocompatible solvent such as DMSO and a water insoluble contrast agent such as tantalum, tantalum oxide and barium sulfate.
U.S. Pat. No. 5,851,508 discloses compositions suitable for use in embolizing blood vessels which comprises an ethylene vinyl alcohol copolymer, a biocompatible solvent such as DMSO and a water insoluble contrast agent such as tantalum, tantalum oxide and barium sulfate.
U.S. Pat. No. 5,695,480 discloses compositions for use in embolizing blood vessels which comprise a biocompatible polymer selected from cellulose acetates, cellulose acetate propionates, cellulose acetate butyrates, ethylene vinyl alcohol copolymers, hydrogels, polyacrylonitrile, polyvinylacetate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid and mixtures thereof, a biocompatible solvent such as DMSO, ethanol and acetone, and a contrast agent such as tantalum, tantalum oxide, tungsten and barium sulfate.
However, in these formulations, the radiopaque contrast agent is suspended in the polymer solution, so that these embolizing compositions are heterogeneous dispersions.
Thus, permanent radiopacity may not be ensured with these compositions because chemical incorporation of the contrast agent into the polymer structure is not achieved and sedimentation of the contrast agent during catheterization or slow release with time in the surrounding areas could occur, which would be a major drawback for clinical follow-up and could lead to serious toxic-effects.
A well-known commercially available formulation of this type is ONYX™, a mixture of ethylene-vinyl alcohol copolymer (EVOH) dissolved in DMSO, with micronized tantalum powder in the liquid polymer/DMSO mixture to provide fluoroscopic visualization.
ONYX™ is delivered through a microcatheter to the target lesion under fluoroscopic control.
Upon contact with body fluid (i.e. blood), the solvent (DMSO) rapidly diffuses away causing in-situ precipitation of the polymer in the presence of the radiopaque contrast agent, thus forming a radiopaque polymeric implant.
ONYX™ is available in a range of liquid viscosities intended to have delivery and precipitation characteristics optimized for the type of lesion being treated.
However, these formulations have the following drawbacks.
These formulations need careful preparation before use, which is time consuming and may lead to application errors.
Further, since the radiopaque contrast agent is suspended in the polymer solution, homogeneous radiopacity may not be ensured with respect to possible sedimentation during embolization. The radiopaque contrast agent also limits non-invasive follow-up imaging by CT scanning because of beam-hardening artifacts. Furthermore, the entrapment of the metallic radiopaque contrast agent is not ensured so that phase separation may occur.
As a consequence, the radiopaque contrast agent does not reflect the position of the polymer and implant visibility may change during radiological imaging follow-up studies. Released metallic radiopaque contrast agents are potentially toxic.
To overcome the drawbacks of formulations containing a radiopaque agent in suspension in the polymer solution, some of the present inventors have focused on the need to provide an intrinsically radiopaque polymer for use as embolizing agent in liquid embolizing compositions.
For this purpose, they have synthesized a iodinated poly(vinyl alcohol) (I-PVA) by grafting iodobenzoyl chloride to poly(vinyl alcohol) via ester linkages and tested such an I-PVA polymer.
The results obtained when such an I-PVA is used in liquid embolizing compositions were reported in a number of publications (see O. Jordan et al., 19th European Conference on Biomaterials, 2005, Sorrento, Italia, “Novel organic vehicles for the embolization of vascular malformations and intracranial aneurysms”; O. Jordan et al., Transactions of the 7th World Biomaterials Congress, Sydney, Australia, 706, 2004, “Novel Radiopaque Polymer for Interventional Radiology”; O. Jordan et al., American Society of Neuroradiology 42nd annual meeting, Seattle, Jun. 5-11, 2004, “Liquid Embolization of Experimental Wide-Necked Aneurysms with Polyvinyl Alcohol Polymer: A New, Nonadhesive, Iodine-Containing Liquid Embolic Agent”; O. Dudeck, O. Jordan et al., Am. J. Neuroradiol., 27:1900-1906, 2006, “Organic solvents as vehicles for precipitating liquid embolics”; O. Dudeck, O. Jordan et al.; Am. J. Neuroradiol., 27: 1849-55, October 2006, “Embolization of Experimental Wide-Necked Aneurysm with Iodine-Containing Polyvinyl Alcohol Solubilized in a Low-Angiotoxicity Solvent”; O. Dudeck, O. Jordan et al., J. Neurosurg. 104: 290-297, February 2006, “Intrinsically radiopaque iodine-containing polyvinyl alcohol as a liquid embolic agent: evaluation in experimental wide-necked aneurysms”) without identifying the I-PVA used.
However, this I-PVA lacks stability with respect to hydrolysis, and when used as embolizing agent, undergoes partial degradation leading to potentially toxic degradation products in the body over time.
Moreover, since the embolic mass is expected to stand for a long duration, sustainable attachment of the iodinated markers is required.
Therefore, the present inventors have focused their research on the need to provide a new iodinated poly(vinyl alcohol) which has an improved stability, and have surprisingly found a new iodinated poly(vinyl alcohol) which has not only an improved stability with respect to hydrolysis, but which is also expected to provide liquid embolizing compositions having higher concentration of embolizing agent, and therefore lower volume of organic solvent due to its unexpected low viscosity in solution, and have thus achieved the present invention.